What exactly causes Parkinson’s disease is far from figured out. But a clue has been lurking in cornfields for years.

The data confirm it: farmers are more prone to Parkinson’s than the general population. And pesticides could be to blame. Over a decade of evidence shows a clear association between pesticide exposure and a higher risk for the second most common neurodegenerative disease, after Alzheimer's. A new study published in Neurology proposes a potential mechanism by which at least some pesticides might contribute to Parkinson’s.

Regardless of inciting factors — and there appear to be many — Parkinson’s ultimately claims dopamine-releasing neurons in a small, central arc of brain called the “substantia nigra pars compacta.” The nigra normally supplies dopamine to the neighboring striatum to help coordinate movement. Through a series of complex connections, striatal signals then find their way to the motor cortex and voila, we move. But when nigral neurons die, motor function goes haywire and the classic symptoms set in, including namely tremors, slowed movements, and rigidity.

Pesticides first came under suspicion as potentially lethal to the nigra in the early 1980s following a tragic designer drug debacle straight out of Breaking Bad. Patients started showing up at Northern California ERs nearly unresponsive, rigid, and tremoring — in other words, severely Parkinsonian. Savvy detective work by neurologist Dr. William Langston and his colleagues, along with the Santa Clara County police, traced the mysterious outbreak to a rogue chemist and a bad batch. He’d been trying to synthesize a “synthetic heroin” — not the snow cone flavorings he claimed — however a powder sample from his garage lab contained traces of an impurity called MPTP. MPTP, it turned out, ravages dopaminergic neurons in the nigra and causes what looks like advanced Parkinson’s. All of the newly Parkinsonian patients were heroin users who had injected the tainted product. And MPTP, it also turned out, is awfully similar in structure to the widely used herbicide paraquat, leading some neurologists to turn their attention to farms and fields.

In 2000, a meta-analysis linked confirmed and presumed pesticide exposure with increased risk of Parkinson’s. Subsequent work supported this connection, including a large 2006 study that followed patients for nine years. The patients exposed to pesticides had a 70% higher incidence of Parkinson’s when the study ended; the risk was the same for exposed farmers and exposed non-farmers, hence some other farm-related factor wasn’t to blame. The study didn’t report on specific toxins, but more recent work out of The Parkinson’s Institute in Sunnyvale, CA, founded by Langston after the MPTP discovery, did. The authors took detailed occupational and exposure histories from farmers and their families. Paraquat upped Parkinson’s risk 2.5-fold. Rotenone was also red-flagged.

Pesticides exert their neurotoxicity in a number of ways. Both paraquat and rotenone appear to wither dopaminergic neurons via free radical production. Free radicals are atoms or molecules with an unpaired electron looking for a partner; they do major cellular damage by pilfering electrons from other molecules, impairing their function. Rotenone may also interfere with the normal neuronal clearance of damaged or degraded proteins. Faulty proteins accumulate, derailing various cellular processes.

The new study, from a team at UCLA, proposes yet another mechanism by which some pesticides might contribute to Parkinson’s. It might also provide a major lead in understanding the disease. The team had previously found that the fungicide benomyl was associated with increased Parkinson’s risk and damaged the brain by inhibiting an enzyme called ALDH that normally helps metabolize fats, proteins and toxins like alcohol (certain ALDH mutation carriers have to take it easy at the bar). ALDH also detoxifies the dopamine metabolite DOPAL. When the enzyme isn’t working properly, DOPAL builds up in neurons and may explain the loss of dopaminergic neurons in Parkinson’s. This time around the authors tested 26 pesticides, first for their influence on ALDH activity in rat neurons and next for any epidemiologic association with Parkinson’s. Eleven pesticides inhibited ALDH at the concentration tested, eight of which could be included in the study based on available histories from 360 rural Californian patients. All eight were associated with an increased Parkinson’s risk and genetic variation in the ALDH2 subtype of the enzyme increased the risk further in those exposed. The findings not only point to new culprit compounds, but reflect the growing appreciation of Parkinson’s as a multifactorial disease, in many cases due to the collusion of both genetic and environmental factors.

At least 10% of Parkinson’cases are now thought to be due primarily to specific gene variants, and estimates suggest that genetics may contribute to upwards of 20% to 50%. Patients with a few specific mutations — common in people of Mediterranean descent — carry a nearly 100% chance of developing the disease. Though, as lead author Dr. Jeff M. Brontstein commented to Scientific American, while a minority of cases might be primarily due to a specific genetic or environmental risk factor, ultimately many if not most cases are likely due to gene-environment interactions. This may explain why there isn’t an epidemic of Parkinson’s in rural areas. Despite the large number of people regularly exposed to pesticides, not everyone has a genetic susceptibility.

This gets incredibly complicated when you consider the possibility of multiple genetic and environmental risk factors working together. It's clear that pesticides wreak havoc on the brain through a variety of mechanisms. Hence farmers and others regularly exposed are at risk for a multipronged, possibly cumulative attack. Certain industrial solvents also appear to bump up Parkinson’s vulnerability. Head trauma, in combination with a particular mutation, does too. And diets high in omega-3 fatty acids, found in fish, plant and seed oils, appear to protect against the disease. The laundry list of risk factors and contributors could explain the varied symptoms experienced by Parkinson’s patients. Some present early in life, some late. For many the classic motor symptoms predominate; others present with non-motor findings like sleep disturbances, constipation and depression. No two cases are identical.

The confusion isn’t just clinical. Recent evidence positions Parkinson’s as one of a number of related neurodegenerative disorders marked by the accumulation of abnormal proteins in the brain, including Alzheimer’s disease and ALS. They all appear partially genetic, partially environmental and probably in many cases both. Neuronal protein accumulations called Lewy bodies — a pathologic hallmark of Parkinson’s — are also found in the brains of Alzheimer’s patients; PD-afflicted brains often contain the amyloid protein aggregates common to Alzheimer’s. It’s a Venn diagram of neurodegeneration.

The new findings further confirm that those whose livelihood relies on repelling pests should pay mind to their increased risk for Parkinson’s, particularly if they have other known risk factors, and take precautions. They can limit exposure and avoid the riskier compounds. They can wear masks, clean up spills and wash up vigorously. Moreover, implicating ALDH in Parkinson’s pathology could represent an important step toward determining a final common pathway on which the various risk factors converge, a potential holy grail for drug development, and ultimately for patients. Rarely are neurologic diseases straight forward, and Parkinson’s has proved no different. But a terribly unfortunate outcome for many in search of heartier, healthier crops may have brought medicine one notch closer to deciphering a frustratingly complex disease.

Are you a scientist who specializes in neuroscience, cognitive science, or psychology? And have you read a recent peer-reviewed paper that you would like to write about? Please send suggestions to Mind Matters editor Gareth Cook, a Pulitzer prize-winning journalist and regular contributor to NewYorker.com. Gareth is also the series editor of Best American Infographics, and can be reached at garethideas AT gmail.com or Twitter @garethideas.

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